Biomolecular characterization of a rat model of lung fibrosis: investigation of its translational potential in Idiopathic Pulmonary Fibrosis (IPF)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, multifactorial and irreversible pulmonary disorder that leads, in a few years, to the progressive deconstruction of lung architecture, until death for respiratory failure or associated comorbidities1. Despite recent progresses, effective pharmacological treatments are not yet available for the treatment of this disease, except for two recently approved drugs that can slow-down lung function decline without stopping or reverting the disease2. Although several models of lung fibrosis have been set-up recently, a fully comprehensive preclinical animal model capable of recapitulating all the characteristic features of human IPF is not yet available. Despite some limitations, the bleomycin (BLM)-induced lung fibrosis murine model is currently viewed as the best preclinical approximation of IPF3,4. The presently limited understanding of IPF, along with the lack of predictive preclinical models have hindered the development of novel effective drugs for this complex disease. In this Ph.D. work, performed in collaboration with Chiesi Farmaceutici, I characterised and optimised a BLM-induced lung fibrosis rat model, with the aim to obtain a multidisciplinary view of the model and expand the currently limited knowledge of the mechanisms underlying lung fibrosis. An additional, related aim was to gain a deeper understanding of the translational potential of the BLM rat model with regard to the human disease, particularly its usefulness for the development of better drugs against IPF. To achieve these goals, a whole transcriptomic analysis and histopathological characterization were performed in two key in-vivo experiments: a time course study and a pharmacological curative study with nintedanib, one of the IPF approved drugs. The multilevel analysis that accompanied these two experiments showed that the pathological condition induced by BLM in the rat model set-up in this Ph.D. thesis work, closely resembled lung fibrosis and was responsive to a reference, clinically approved IPF drug. Moreover, transcriptomic analyses performed in this experimental set-up revealed the existence of specific gene signatures, enriched in pathways and processes that hold great promise as new IPF biomarkers and therapeutic targets.